CIN2 Regression Rates Underestimated

Active surveillance better than excision for some patients

Action Points

The majority of cervical intraepithelial neoplasia grade 2 (CIN2) lesions, particularly in women <30 years old, regress spontaneously, according to a meta-analysis, suggesting to researchers that active surveillance, rather than immediate intervention, is justified in selected women.

Recognize that even though these data provide the best information to date, a 50-60% chance of regression still means taking a gamble that surveillance is simply delaying treatment, and even a small risk of cancer may still be unacceptable to some.

More untreated cervical intraepithelial neoplasia grade 2 lesions (CIN2) than previously thought regress spontaneously, making it "of utmost importance" to treat only those patients at significant risk of progressive disease, according to researchers.

In a meta-analysis of 36 studies involving 3,160 women with CIN2 who were actively monitored for at least 3 months, 50% of the lesions regressed spontaneously, 32% persisted, and just under one in five (18%) progressed to CIN3 or worse within 2 years.

The rate of regression was even higher (60%) in a subgroup of 1,069 women younger than age 30, Maria Kyrgiou, MD, PhD, of Imperial College London, and colleagues reported online in The BMJ.

In addition, the rates of persistence and progression were lower in younger women than in women older than 30 (23% and 11%, respectively, versus 44% and 23%).

"The results of our analysis show higher rates of regression and lower rates of progression of histologically confirmed CIN2 lesions than previously reported, particularly in women age less than 30," the study authors wrote. "Conservative management with active surveillance, instead of immediate local excision, is therefore justified in selected women, especially if further pregnancies are considered and compliance with surveillance is likely to be high."

In women with disease that persists beyond 2 years, "treatment is likely to be warranted," the researchers said.

Their meta-analysis included studies published between January 1, 1973 (when the CIN grading system was first introduced) and August 20, 2016. The team looked at rates of regression, persistence, or progression of CIN2 and adherence to follow-up at 3, 6, 12, 24, 36, and 60 months in women with histologically confirmed CIN2; all were managed with active surveillance.

There were only 13 stage 1A1 (0.4%) and two more advanced (0.06%) invasive cases, and most were in women older than age 30. After 24 months of follow-up, the rate of non-compliance in prospective studies was about 10%.

"CIN2 on a colposcopically directed cervical biopsy has been considered the clinical cut-off to proceed to treatment," Kyrgiou et al noted, adding that local excision of the cervix has been proven effective for the treatment of CIN2 and CIN3. Treatment also increases the risk of pregnancy complications, preterm birth, and mid-trimester loss in women who go on to conceive after treatment.

Other studies have documented high spontaneous CIN2 regression rates, particularly in young women, but this is the first systemic review to explore "the clinical course of histologically confirmed CIN2 lesions monitored conservatively," the investigators said.

In an accompanying editorial, Maggie Cruickshank, MD, of the University of Aberdeen in Scotland, acknowledged that these findings "provide the best information to date on likelihood of regression or progression after a diagnosis of CIN."

As did the study authors, she advised that the findings be interpreted with caution -- noting, however, the heterogeneity of the studies reviewed, the increased likelihood of misclassification, and the high risk of bias.

"Knowing that the chance of regression is 50%-60% still means taking a gamble that surveillance is simply delaying treatment," Cruickshank wrote. "Even a small risk of cancer (0.5% in this study) may still be unacceptable to some."

The data on "active surveillance" were also limited, she continued. "We do not yet have a clear definition of active surveillance in the context of CIN2." Clarification is also needed about which interventions should be used, and how often, "to confirm regression, identify persistence, or recommend treatment for progression."

In some cases, a patient's ability to access surveillance and follow-up appointments may tip the balance in clinical decision-making. "Where women cannot afford choice, a 50% rate of persistence or progression may justify immediate treatment of CIN2 in women ages more than 30 years."

Better understanding about the rates of progression in CIN2 is unlikely to prove helpful in managing patients' concerns, Cruickshank warned, adding that clinicians will need to present information on both surveillance and treatment in a clear, concise way to help patients make fully informed choices.

Asked for her perspective, Noelle Gillette Cloven, MD, of Texas Oncology in Fort Worth, who was not involved with the study, told MedPage Today via email: "Over-treatment in young women should be avoided, as there are increased risks of pregnancy complications after excisional procedures. It is recommended that women who choose active surveillance undergo repeat colposcopy and Pap test every 6 months for the first 2 years."

It is also vital that patients understand the importance of follow-up and avoid high-risk behaviors, especially smoking, Cloven added.

Women with unexplained symptoms such as irregular bleeding require treatment, as do those who are at high risk because they are HIV-positive, for example. "If the dysplasia persists, treatment is indicated, and consideration could be given to testing for high HPV subtypes 16 and 18. If these are negative, regression rates may be higher."

Kyrgiou and co-authors noted that the estimated incidence of CIN2/3 diagnosed annually in developed countries is 1.5 per 1,000 women, which rises to an estimated 8.1 per 1,000 women in those ages 25 to 29.

The study was funded by the Sigrid Jusélius Foundation, the British Society of Colposcopy Cervical Pathology, the Imperial College Healthcare Charity, the Genesis Research Trust, the Imperial Healthcare NHS Trust National Institute for Health Research Biomedical Research Centre, the Academy of Finland, the Helsinki and Uusimaa Hospital District, and the Jane and Aatos Erkko Foundation.

Kyrgiou and co-authors, as well as Cruickshank, reported having no conflicts of interest.

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